"Anybody who has been verbally abused or physically abused will spend a great deal of their life rebuilding their esteem," Winfrey said as the conversion began on a serious note before about 3,000 students and others at Emens Auditorium on the Muncie campus.
Winfrey recounted being physically beaten as a child, saying it was a cultural experience many African-American children went through. She also said was raped and molested.
"You're an extraordinary person who lived through hell," Letterman said. "You were not consumed, you prevailed."
Winfrey contrasted her childhood experience with Letterman's suburban upbringing, which the two compared to a 1960s sitcom, the Ball State Daily News reported (http://bit.ly/TqUROz).
After nearly two hours on stage, Ball State President Jo Ann Gora walked onstage as if to signal that their time was up.
"May we help you?" Letterman joked, adding that Gora acted like "she owns the place."
The two continued, with Winfrey taking questions from the audience.
Letterman and Winfrey feuded for more than 10 years, but it ended in 2005 when Winfrey appeared on Letterman's "The Late Show" on CBS.
She had told Time magazine in 2003 that she wouldn't go on his show because she has been "completely uncomfortable" as the target of his jokes, including the awkward "Oprah, Uma. Uma, Oprah" introduction.
Hundreds of Ball State University students camped out overnight earlier this month to get free tickets for the event.